| Description |
Tirzepatide (LY3298176) was developed as a dual agonist to both GLP-1 and gastric inhibitory polypeptide (GIP) receptors (Frias et al., 2018). Similar to GLP-1, GIP is an incretin hormone that functions to induce insulin secretion. |
| Uses |
Tirzepatide is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. |
| Mechanism of action |
It works to stimulate first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner. Tirzepatide was also shown to delay gastric emptying, lower fasting and postprandial glucose concentration, decrease food intake, 4 and reduce body weight in patients with type 2 diabetes. |
| Pharmacology |
Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well. |
| Side effects |
The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies that have been approved for the treatment of obesity. This said, reported side effects were considerable, especially as dosage levels increased. The most common adverse events were nausea (~30%), diarrhea (~20%), constipation (~15%) and vomiting (~10%).
If tirzepatide gets approved as a both a blood glucose control and anti-obesity agent, it could become a blockbuster drug. However, this isn’t a sure thing. It will have to overcome pricing and reimbursement obstacles, which have plagued similar treatments. |
| Mode of action |
Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist. Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor. However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion. Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage. |
| Clinical claims and research |
Tirzepatide (Eli Lilly), a novel, once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 RA combination drug, has been developed to treat patients with T2DM. The manufacturer (Eli Lilly) announced the submission of a biologics license application with priority review to the FDA for T2DM on October 27, 2021, with a decision expected in mid-2022. |
